Alcohol abuse is a major health problem costing millions of dollars annually in treatment and lost productivity. The basic mechanisms that lead to alcohol craving are unclear. Peptides related to ingestive behavior appear to be important to control of alcohol ingestion. Studies with neuropeptide Y(NPY)-knockout mice demonstrate that animals lacking NPY consume more alcohol, while mice that overexpress NPY have decreased alcohol intake. Moreover, NPY is found to be lower in regions of the limbic system such as the amygdala, hippocampus and prefrontal cortex of alcohol preferring rats. Collectively, these data indicate that alcohol preference is inversely correlated to NPY levels in the brain. Our research plan examines the role of NPY in 3 rodent models with contrasting behaviors relative to alcohol intake. Two models, the Zucker fatty and the area postrema-lesioned rat, have been the focus of many studies of energy balance and food intake. These studies revealed that these models have elevated levels of hypothalamic NPY. Studies of alcohol preference indicate that these rats tend to avoid alcohol compared to their respective controls. Thus, in accordance with the proposed role of NPY in the regulation of alcohol intake. Use of antisense technology, immunoneutralization or receptor antagonists to attenuate the activity of NPY in these models should increase alcohol preference. The third model is the Taste Aversion-Resistant (TAR) rat. This rat model was developed to be resistant to conditioned taste aversion. It has also been found that the TAR rat has a strong alcohol preference. Neurochemical studies in the TAR rat have revealed differences in biogenic amine levels and in the efficiency of the serotonin transporter. However, the activity of neuropeptides in this model of alcohol preference has not been explored. Thus, initial studies with this model will correlate the activity of limbic NPY systems with alcohol intake. We predict that neuropeptide Y levels are lower in the TAR rat. Manipulations to elevate NPY in this model should decrease alcohol intake. The TAR rat, contrasted with the Zucker fatty and area postrema-lesioned rat, offers an interesting and unique opportunity to study the role of neuropeptides important to ingestive behavior in the control of alcohol intake. Our initial studies focus on NPY, but future studies will involve gastrointestinal peptides as well as other central neuropeptides reported to alter ingestive behavior. Manipulation of these neuropeptides will provide insights into controls of alcohol intake as well as how peptides important to ingestive behavior impact reward pathways in the brain.